To achieve continuous delivery of the protein or peptide in vivo, a sustained release or sustained delivery formulation is desirable to avoid the need for repeated administrations. One approach for sustained drug delivery is by microencapsulation, in which the active ingredient is enclosed within a polymeric membrane to produce microparticles.
It has been shown that one can encapsulate a biologically active or pharmaceutically active agent within a biocompatible, biodegradable wall forming material such as a polymer, to provide sustained or delayed release. In these methods the agent or drug is typically dissolved, dispersed or emulsified, using stirrers, agitators, or other dynamic mixing techniques, in one or more solvents containing the wall forming material. The solvent is then removed resulting in the formation of microparticles encapsulating the agent or drug. These microparticles can then be administered to a patient.
The importance of biocompatible and/or biodegradable polymers as carriers for parenteral drug delivery systems is now well established. Biocompatible, biodegradable, and relatively inert substances such as poly(lactide) (PLA) or poly(lactide-co-glycolide) (PLGA) microspheres or films containing the active agent to be administered are commonly utilized sustained-release devices (for review, see M. Chasin, Biodegradable polymers for controlled drug delivery. In: J. O. Hollinger Editor, Biomedical Applications of Synthetic Biodegradable Polymers CRC, Boca Raton, Fla. (1995), pp. 1-15; T. Hayashi, Biodegradable polymers for biomedical uses. Prog. Polym. Sci. 19 4 (1994), pp. 663-700; and Harjit Tamber, Pål Johansen, Hans P. Merkle and Bruno Gander, Formulation aspects of biodegradable polymeric microspheres for antigen delivery Advanced Drug Delivery Reviews, Volume 57, Issue 3, 10 Jan. 2005, Pages 357-376).
However, there still exist many challenges to the design of delivery systems for active agents. A basic requirement for such delivery systems is that the materials used are acceptable for parenteral application. As mentioned above, it is desirable that the materials used are biodegradable for formulations intended for repeated administration. Another generally desirable quality is biocompatibility: the materials should be tolerated well and biodegradation should produce innocuous compounds that are either eliminated from the body or incorporated in the intermediary metabolism. The list of materials used generally for manufacture of parenteral preparations is limited and is shorter still for parenteral protein formulations.
Another desirable attribute is sufficiently good control of the release of the encapsulated active agent. It is generally important to maintain the concentration of the active agent within an effective window for a time period sufficient to achieve the desired effect and to avoid excessive concentrations, which may lead to side effects or untoward results. It is often difficult to achieve the desired release kinetics with monolithic microparticles as the fraction of the active agent released within the first day after administration is often dependent on the loading level of the drug.
Yet another desirable characteristic of sustained delivery technologies, particularly when applied to the delivery of macromolecules, is that the integrity of the active agent is maintained during manufacture. This is often a difficult challenge as most protein and peptide drugs are dependent on a three dimensional conformation for their bioactivity and that conformation can easily be compromised. For example, most of the polymers that are used to manufacture controlled release parenteral preparations are not soluble in water and consequently the protein or peptide is exposed to an organic solvent in the encapsulation step. Examples of other undesireable stresses that are associated with manufacturing of controlled release preparations that may compromise the integrity of any particular active agent are high shear forces used to form droplets of the polymer solution in an continuous phase, exposure to polymerization reactions, high temperatures and undesirably low or high pH values.
Another desirable attribute of sustained release modalities is that the integrity of the active agent, particularly proteins or peptides, is retained within the microparticles during release. Depending on the chosen duration of release, this period can be from a few days up to several months. For conventional polymer matrix systems formed of PLGA the acidic microenvironment formed during biodegradation of the polymer may degrade active agents incorporated therein during in vitro and in vivo incubation.
The prior art describes various sustained delivery compositions and methods for making them, for example, U.S. Pat. Nos. 5,916,597; 5,019,400; 5,922,253; and 6,531,154. The in vivo release of incorporated active agents from biocompatible and biodegradable polymers is, in many cases, initially high or low, and therefore non-uniform throughout the life of the delivery device. Additionally, microencapsulation with polymers tends to provide long term sustained delivery of peptides ranging from two weeks to nine months or longer whereas there is a need for shorter term delivery profiles for certain medicaments. Thus, there is a need in the art for sustained release compositions with release profiles of less than about a week or two.